Literature on CytoSorb -Therapy and. Related Topics

Transcription

1 Literature on CytoSorb -Therapy and Related Topics Rating: very helpful and worth reading helpful and worth reading helpful and worth reading to a limited extent Literature List CytoSorb 1 Nov 18

2 Table of Contents New Publications: Clinical data Studies Sepsis Cardiac surgery Other indications Case series Sepsis Cardiac surgery Other indications Case reports Sepsis Cardiac surgery Liver Myoglobinemia Other indications Pre-Clinical data Animal models In vitro data Background & Reviews Literature List CytoSorb 2 Nov 18

3 New Publications 1. Clinical Data 1.1 Studies Sepsis NEW; Extracorporeal cytokine adsorption in septic shock: A proof of concept randomized, controlled pilot study Hawchar F, László I, Öveges N, Trásy D, Ondrik Z, Molnar Z Journal of Critical Care 2018; epub Other Indications NEW, Snake bite induced sepsis with multi organ failure successfully treated with Extracorporeal Cytokine Adsorption Device (ECAD) therapy along with standard of care - a case series Sathe P, Sakhavalkar P, Borse R, Parathody A, Huparikar A, Rayte N IJMDAT 1(2): e Backgrounds and Reviews NEW; Hemoadsorption with CytoSorb((R)) Poli EC, Rimmele T, Schneider AG Intensive Care Med 2018; epub NEW; Extracorporeal techniques for the treatment of critically ill patients with sepsis beyond conventional blood purification therapy: the promises and the pitfalls. Ankawi G, Neri M, Zhang J, Breglia A, Ricci Z, Ronco C. Crit Care 2018; 22(1): 262 Literature List CytoSorb 3 Nov 18

4 1. Clinical data 1.1. Studies Sepsis NEW; Extracorporeal cytokine adsorption in septic shock: A proof of concept randomized, controlled pilot study Hawchar F, László I, Öveges N, Trásy D, Ondrik Z, Molnar Z Journal of Critical Care 2018; epub ; The aim of this proof of concept, prospective, randomized pilot trial was to investigate the effects of extracorporeal cytokine removal with CytoSorb applied as a standalone treatment in 20 patients with early (<24hrs) septic shock. Inclusion criteria also included: on mechanical ventilation; norepinephrine >10 μg/min; procalcitonin (PCT) >3 ng/ml; and without the need for renal replacement therapy (RRT). Patients were randomized into CytoSorb (n=10) for 24 hours or Control groups (n=10). Clinical and laboratory data were recorded at baseline, 12, 24 and 48 hrs. Overall SOFA scores did not differ between the groups, however, in the CytoSorb-group norepinephrine requirements and PCT concentrations decreased significantly (p=0.016 and p=0.004 respectively). Big-endothelin-1 concentrations were also significantly lower in the CytoSorb group (p = 0.003). All patients in the CytoSorb group survived to 48 hrs (2 patients in the control arm died before the 48 hr period). The authors note that the level of norepinephrine dose for the CytoSorb group was almost twice that of the controls at study entry. There were no CytoSorb therapy-related adverse events. This is the first trial to investigate the effects of early extracorporeal cytokine adsorption treatment in septic shock patients, used without RRT. CytoSorb was found to be safe with significant effects on norepinephrine requirements, PCT and Big-endothelin-1 concentrations when compared to controls. The effect of a novel extracorporeal cytokine hemoadsorption device on IL-6 elimination in septic patients: A randomized controlled trial Schadler D, Pausch C, Heise D, Meier-Hellmann A, Brederlau J, Weiler N, Marx G, Putensen C, Spies C, Jorres A, Quintel M, Engel C, Kellum JA, Kuhlmann MK PLoS One 2017; 12(10): e ; This first clinical study ever conducted with CytoSorb ( ) was a randomized, controlled, open-label, multicenter trial that reported on the use of CytoSorb for 6 hours daily for 7 days in 97 mechanically ventilated patients with severe sepsis or septic shock and acute respiratory distress syndrome (ALI / ARDS). The study was not able to detect differences in systemic plasma IL-6 levels between the two groups (n = 75; p = 0.15) although significant IL-6 elimination, averaging between 5 and 18% per blood pass throughout the entire treatment period was recorded. There was also no statistically significant difference in the secondary outcomes multiple organ dysfunction score, ventilation time and time course of oxygenation. The proportion of Literature List CytoSorb 4 Nov 18

5 patients receiving renal replacement therapy at the time of enrollment was higher in the treatment group (31.9%) compared to the control group (16.3%). After adjustment for patient morbidity and baseline imbalances, no association of hemoperfusion with mortality was found (p = 0.19). Extracorporeal Cytokine Elimination as Rescue Therapy in Refractory Septic Shock - a Prospective Single-Center Study Friesecke S, Stecher SS, Gross S, Felix SB, Nierhaus A Journal Artif Organs 2017; 20(3): ; Mortality from refractory septic shock may reach % despite optimum therapy. In this study cytokine adsorption using CytoSorb in addition to regular therapy was studied prospectively in 20 patients with refractory shock (defined as increasing vasopressor dose required to maintain mean arterial blood pressure above 65 mmhg or increasing lactate levels despite protocol-guided shock therapy for six hours). CytoSorb treatment was started after 7.8 ± 3.7 hours of shock therapy. Following the initiation of CytoSorb, noradrenaline dose could be significantly reduced after 6 (p=0.03) and 12 hours (p=0.001). Lactate clearance improved significantly. Shock reversal was achieved in 13 (65%) patients; 28-day survival was 45% (predicted mortality from the SOFA score was >80%). The use of CytoSorb adsorption therapy resulted in shock reversal in two thirds of these particularly difficult to treat patients Cardiac surgery Hemoadsorption does not Affect Hemolysis During Cardiopulmonary Bypass. Bernardi MH, Rinoesl H, Ristl R, Weber U, Wiedemann D, Hiesmayr MJ. ASAIO J 2018; epub Cardiopulmonary bypass (CPB) induces hemolysis, which manifests as plasma free hemoglobin (pfhb), which increases the risk of post-operative complications including decreased blood flow and organ damage. Haptoglobin scavenges hemoglobin, but has limited capacity. This is a post hoc analysis from the previously published study (Bernardi MH et al. Effect of hemoadsorption during cardiopulmonary bypass surgery - a blinded, randomized, controlled pilot study using a novel adsorbent. Crit Care 2016; 20(1): 96) and investigated whether the use of CytoSorb affected hemolysis during CPB. A total of 35 patients undergoing elective CPB surgery with expected CPB duration of more than 120 min were included in the analysis where CytoSorb was used (17 in the intervention group and 18 in the control group). Postoperative pfhb levels were not significantly different between the groups, however, there were statistically significant differences between the treatment and control groups in the median levels of haptoglobin (58.4 vs mg/dl, respectively; P < 0.01) and lactate dehydrogenase (353.0 vs U/L, respectively; P < 0.05) on postoperative day 1. Although the study did not find a statistically significant effect on hemolysis in patients treated with hemoadsorption, statistically significant lower haptoglobin levels and higher Literature List CytoSorb 5 Nov 18

6 secondary hemolysis markers on postoperative day 1 in patients not treated with the device may be an indication of some moderate positive effect of CytoSorb. Impact of intraoperative cytokine adsorption on outcome of patients undergoing orthotopic heart transplantation an observational study Nemeth E, Kovacs E, Racz K, Soltesz A, Szigeti S, Kiss N, Csikos G, Koritsanszky KB, Berzsenyi V, Trembickij G, Fabry S, Prohaszka Z, Merkely B, Gal J. Clinical Transplantation 2018; 32(4):e13211 The aim of this study was to assess the influence of intraoperative cytokine adsorption using CytoSorb on the perioperative vasoplegia, inflammatory response and outcome during orthotopic heart transplantation (OHT). Patients were separated into the cytokine adsorption (CA) treated group or historic controls. In the 16 matched pairs, the median noradrenaline requirement was significantly less in the CA-treated patients than in the controls on the first and second postoperative days (P=0.039 and P=0.047). The inflammatory responses (assessed by PCT and CRP) were similar in the two groups. There was a trend towards shorter length of mechanical ventilation and intensive care unit (ICU) stay in the CA-treated group compared to the controls. No difference in adverse events was observed, however, the frequency of renal replacement therapy was significantly less in the CA-treated than in controls (P=0.031). In summary, intraoperative CytoSorb during OHT proved to be safe and was associated with reduced vasopressor demand and less frequent renal replacement therapy with a favorable tendency in length of mechanical ventilation and ICU stay. Use of cytokine filters in cardiopulmonary bypass machines (Einsatz eines Zytokinfilters in die Herz-Lungen-Maschine) Deppe AC, Weber C, Choi YH, Wahlers T Z Herz- Thorax-Gefäßchir 2016;30(4): Abstract and article in German, abstract only in English. Cardiac surgery using a cardiopulmonary bypass (CPB) machine induces a systemic inflammatory reaction due to activation of multiple inflammatory cascades which may result in systemic inflammatory response syndrome (SIRS). Activation of various inflammatory mediators, such as interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) can lead to postoperative complications, organ dysfunction, morbidity and mortality. The effect of adsorption of cytokines using CytoSorb with a CPB machine is evaluated in this prospective, observational pilot study to determine the clinical impact on the serum levels of IL- 6, IL-8 and TNF-alpha. This pilot study includes 300 patients planned for elective surgical myocardial revascularization, split into 3 groups; 100 patients with onpump myocardial revascularization with CytoSorb; on-pump myocardial revascularization without CytoSorb and off- pump myocardial revascularization. Primary outcome measures are IL-6, IL-8, TNF- alpha, complement C3/C4, Literature List CytoSorb 6 Nov 18

7 leucocyte counts and C-reactive protein. Secondary outcome measures are length of intensive care unit and total hospital stay, duration of ventilation, duration of catecholamine therapy, kidney injury as well as major adverse cardiac and cerebrovascular events. Interim analysis after 60 % of patients had been included revealed a well- balanced group allocation of patients. In the CytoSorb group IL-6 values are decreased, whereas TNF-alpha values are comparable between the three groups. There was reduced sternal wound infections and lower usage of antibiotics in the CytoSorb group. The use of the CytoSorb filter during CPB is safe compared with standard procedure and without technical difficulties. CytoSorb reduces cytokine load and seems to attenuate the inflammatory response. Effect of hemoadsorption during cardiopulmonary bypass surgery - a blinded, randomized, controlled pilot study using a novel adsorbent Bernardi MH, Rinoesl H, Dragosits K, Ristl R, Hoffelner F, Opfermann P, Lamm C, Preißing F, Wiedemann D, Hiesmayr MJ, Spittler A Crit Care 2016;20(1):96 Objective of this blinded, randomized, controlled single-center trial in 46 adult patients undergoing elective coronary artery bypass graft [CABG], valve surgery, or combined procedure with an expected CPB duration of more than 120 min, was to test CytoSorb installed in the cardiopulmonary bypass (CPB) circuit (intraoperative usage) with changes in pro- and anti-inflammatory cytokines levels, inflammation markers, and differences in patients' perioperative course. The authors did not find any reduction in the proinflammatory response between patients and therefore no changes in their perioperative course. Of note, only the least sick cohort of patients undergoing relatively low-risk cardiac surgery were included in this study. Therefore the observed inflammatory response was only moderate even in the control group. The use and installation of the CytoSorb adsorber in a CPB circuit was technically feasible, and no adverse device-related side effects occurred. The results showed that albumin and platelet levels are not significantly affected by CytoSorb. There was a possible protective effect of the observed elevated IL- 10 levels postoperatively, which have been associated with lower mortality in previous studies. After safety and feasibility have been demonstrated, patient groups with the best clinical benefit from CytoSorb need to be identified. RECCAS - REmoval of Cytokines during CArdiac Surgery: study protocol for a randomised controlled trial Baumann A, Buchwald D, Annecke T, Hellmich M, Zahn PK, Hohn A Trials 2016;17(1):137 On-pump cardiac surgery triggers a significant postoperative systemic inflammatory response, sometimes resulting in multiple-organ dysfunction associated with poor clinical outcome. CytoSorb may attenuate this inflammatory response. The aim of this single-centre randomised, two-arm, Literature List CytoSorb 7 Nov 18

8 patient-blinded RECCAS trial is to assess the efficacy of intraoperative CytoSorb use during cardiopulmonary bypass (CPB) to reduce the proinflammatory cytokine (i.e. IL-6) burden during and after on-pump cardiac surgery, as well as to evaluate the effects on postoperative organ dysfunction and outcomes in high risk patients. Differences in secondary outcome variables between the study groups may give rise to further studies and may lead to a better understanding of the mechanisms of CytoSorb treatment Other indications International registry on the use of the CytoSorb(R) adsorber in ICU patients : Study protocol and preliminary results. Friesecke S, Trager K, Schitter GA, Molnar Z, Bach F, Kogelmann K, Bogdanski R, Weyland A, Nierhaus A, Nestler F, Olboeter D, Tomescu D, Jacob D, Haake H, Grigorjev E, Nitsch M, Baumann A, Quintet M, Schott M, Kielstein JT, Meier- Hellmann A, Born F, Schumacher U, Singer M, Kellum J, Brunkhorst FM. Med Klin Intensivmed Notfallmed 2017; epub This is the third interim analysis from the CytoSorb clinical registry where the aim is to record the use of CytoSorb adsorbers in critically ill patients under real-life conditions. It records all relevant information in the course of product use, including diagnosis, comorbidities, course of the condition, treatment, concomitant medication, clinical laboratory parameters, and outcome. Data available from the start of the registry on May 18, 2015 to November 24, 2016 (122 centers; 22 countries) were analyzed, of whom 20 centers from four countries provided data for a total of 198 patients (mean age / years). In all, 192 (97.0%) had 1 to 5 Cytosorb adsorber applications. Sepsis was the most common indication for CytoSorb treatment (135 patients). Mean APACHE II score in this group was /- 8.4 [range 15-52] with a predicted risk of death of 78%, whereas the observed mortality was 65%. There were no significant decreases in the SOFA scores after treatment, however interleukin- 6 levels were markedly reduced after treatment (median 5000 pg/ml before and 289 pg/ml after treatment, respectively). This third interim report demonstrates the feasibility of the registry with excellent data quality and completeness from 20 study centers. Patient numbers are still small; however disease severity is remarkably high and suggest that adsorber treatment might be used as a potentially beneficial treatment in life-threatening situations. Treating physicians rated the condition of the patients as much or very much improved in approximately 50% of cases and reported a very favorable safety profile with no device-associated side effects. Feasibility study of cytokine removal by hemoadsorption in brain-dead humans Kellum JA, Venkataraman R, Powner D, Elder M, Hergenroeder G, Carter M Crit Care Med 2008;36(1): Literature List CytoSorb 8 Nov 18

9 Through numerous mechanisms, brain death is associated with a massive release of proinflammatory cytokines, detectable both in blood and transplantable organs. This increased inflammatory response has been associated with poor allograft function before and after transplantation. Therefore, this in vivo study examines the feasibility of hemoadsorption (using CytoSorb) to remove cytokines in 8 brain-dead humans Case series Sepsis Effect of hemoadsorption for cytokine removal in pneumococcal and meningococcal sepsis Leonardis F, De Angelis V, Frisardi F, Pietrafitta C, Riva I, Martino Valetti T, Broletti V, Marchesi G, Menato L, Nani R, Marson F, Fabbris M, Cabrini L, Colombo S, Zangrillo A, Coniglio C, Stalteri L, Giuliani G, Dalmastri V, Gordini G, La Manna G. Case Reports in Critical care 2018; In this case series five patients with pneumo (n=2) or meningo-coccal sepsis (n=3) were treated with a CytoSorb adsorber for cytokine removal. In these patients bacteria enters the blood stream, proliferate and provoke an immune and inflammatory reaction which may rapidly lead to fulminant septic shock. These bacteria may also cross the blood brain barrier causing bacterial meningitis. Due to the severity of the disease process including coagulation disorders, poor outcome, typically including necessity for extensive amputation of extremities, and a high mortality rate is not uncommon. All patients showed progressive stabilization in hemodynamics along with rapid and marked reduction of catecholamine dosages, stabilization in metabolic disorders and less than expected loss of extremities. None of the patients died within the first 28 days. In these patients, use of CytoSorb for cytokine removal seemed to be a valid and safe therapy in the management of meningococcal and pneumococcal diseases and may contribute to patient stabilization and prevention of severe sequelae. Hemoadsorption by CytoSorb in septic patients a case series Kogelmann K, Jarczak D, Scheller, M, Drüner M Crit Care 2017;21:74 In this case series the authors evaluated the impact of CytoSorb, used as adjunctive therapy, on hemodynamics and clinically relevant outcome parameters in 26 septic shock patients with a need for renal replacement therapy. Treatment was associated with hemodynamic stabilization and a reduction in blood lactate levels. Actual mortality was lower than that predicted by the APACHE II score. This effect was more pronounced in patients where therapy was started within 24 hours after the diagnosis of sepsis. Medical patients seemed to benefit more than post-surgical patients in terms of Literature List CytoSorb 9 Nov 18

10 survival. Treatment with the CytoSorb was safe and well tolerated with no device related adverse events during or after the treatment sessions. Case series of patients with severe sepsis and septic shock treated with a new extracorporeal sorbent Laddomada T, Doronzio A, Balicco B Crit Care 2016;20(Suppl 2):P193 In this case series of 8 patients with severe sepsis and septic shock treated with CytoSorb, the influence of CytoSorb on clinical outcomes such as mean arterial pressure (MAP), vasopressor need and inflammatory markers, e.g. procalcitonin (PCT) was anayzed. There was an overall improvement in MAP with a rapid reduction in vasopressor dosages. Moreover, CytoSorb treatment in combination with CRRT was associated with a marked decrease in PCT levels and an improvement in renal function. In non-survivors, MAP was hard to stabilize and decreased, and there was an aggravation in the patients overall condition. The authors conclude that the timely use of CytoSorb in combination with standard therapy may have benefits in improving hemodynamics and help with more rapid stabilization. Early report: The use of Cytosorb haemabsorption column as an adjunct in managing severe sepsis: initial experiences, review and recommendations Morris C, Gray L, Giovannelli M Journal of Intensive Care Society 2015;16(3): In this article the authors describe the use of CytoSorb hemoadsorption device in 2 patients with overwhelming sepsis following community acquired pneumonia. In addition, the authors consider the experience and evidence supporting the use of CytoSorb in clinical practice. They state that while Cytosorb haemoabsorption is mechanistically distinct from other extracorporeal therapies in sepsis and appears effective in reducing inflammatory cytokines during sepsis, much of the basic science and clinical benefits remain unclear. Suggestions for future research and how Cytosorb could be incorporated into practice are provided. Clinical experience of using a novel extracorporeal cytokine adsorption column for treatment of septic shock with multiorgan failure Sathe P, Sakhavalkar P, Kumar S, Choudhary S Crit Care 2015;19 (Suppl 1):P130 In aim of this retrospective case series in 19 ICU patients treated with standard care plus CytoSorb as an adjuvant therapy was to analyze clinical safety. In a subgroup of patients where CytoSorb was used, selection of timing for Literature List CytoSorb 10 Nov 18

11 initiation, number of CytoSorb devices required per patient, and selective markers to identify its initiation was studied. All of the patients had high predicted mortality (APACHE II >17, SOFA >11). Four patients survived with use of CytoSorb therapy. Importantly, three of them were treated early (<24 hours of admission). APACHE scores decreased >5 points in five patients after a single application of CytoSorb therapy. Of those patients who died, the majority (n = 11) were given CytoSorb treatment only once and seven were treated late (>24 hours). The authors state that a better outcome could be expected if therapy was initiated earlier (<24 hours). However, future studies are needed to clarify the role of CytoSorb in patients with MOF/septic shock Cardiac surgery Blood Purification With CytoSorb in Critically Ill Patients: Single-Center Preliminary Experience. Calabro MG, Febres D, Recca G, Lembo R, Fominskiy E, Scandroglio AM, Zangrillo A, Pappalardo F Artif Organs 2018; epub In this retrospective case series study in 40 critically ill cardiac surgery patients with multiple organ failure the use of CytoSorb therapy inserted into either the extracorporeal membrane oxygenation (ECMO) circuit (19 pts), or as standalone hemoperfusion (21 pts) was evaluated for clinical outcomes. The series included patients with cardiogenic shock (28), septic shock (2), acute respiratory distress syndrome (9), and liver failure (1). Of the 19 patients who underwent ECMO, 11 had an intra-aortic balloon pump, 9 with Impella, and 6 had a ventricular assist device. Patients received at least one CytoSorb treatment (median number of filters used 2). After CytoSorb treatment, total bilirubin, lactate, Creatinine phosphokinase (CPK) and lactate dehydrogenase (LDH) all decreased significantly as did the vasoactive-inotropic score. Thirtyday mortality was 55% and ICU mortality was 52.5% with an expected ICU mortality of 80% according to the sepsis-related organ failure assessment (SOFA) score. This case series shows that CytoSorb treatment is effective in reducing bilirubin, lactate, CPK and LDH, in critically ill patients mainly due to cardiogenic shock. No device related adverse events were observed. Hemoadsorption treatment of patients with acute infective endocarditis during surgery with cardiopulmonary bypass - A case series Träger K, Skrabal C, Fischer G, Datzmann T, Schroeder J, Fritzler D, Hartmann J, Liebold A, Reinelt H Int Art Organs J 2017;40(5):240-9 In this retrospective case series, the authors describe 39 cardiac surgery patients with proven acute infective endocarditis undergoing valve replacement during cardiopulmonary bypass surgery in combination with Literature List CytoSorb 11 Nov 18

12 intraoperative CytoSorb hemoadsorption. In comparison an historical group of 28 similar patients treated without the use of intraoperative CytoSorb were evaluated. CytoSorb treatment was associated with a reduction in postoperative cytokines (IL6, IL8) and clinical metabolic parameters (lactate and base excess). Moreover, in comparison to the non-cytosorb group, the CytoSorb patients showed hemodynamic stability (higher mean arterial pressure) during and after the operation with the need for vasopressors (norepinephrine and epinephrine) being lower within hours after completion of the procedure. The authors conclude that these improvements in patient outcome could be attributed to the use of the CytoSorb adsorber treatment and that its use is a potentially promising therapeutic option for this group of critically-ill patients leading to cytokine reduction, improved hemodynamic stability and organ function. Treatment of post-cardiopulmonary bypass SIRS by hemoadsorption: a case series Traeger K, Fritzler D, Fischer G, Schröder J, Skrabal C, Liebold A, Reinelt H Int J Artif Organs 2016;39(3):141-6 Objective of this case series in 16 adult patients undergoing standard or emergency cardiothoracic surgery procedures with prolonged CPB time, developing post-cpb SIRS over the course of the first post-operative 24 hours was to test the effect of CytoSorb on changes of inflammatory cytokines levels, metabolic parameters hemodynamic variables, and patient outcome. Treatment of these patients with CytoSorb in conjunction with CVVHD was associated with decreases in the proinflammatory cytokines, IL-6 and IL-8, as well as a clear stabilization of hemodynamic, metabolic and organ function parameters. All patients with an APACHE score of up to 30 survived. This is the first case series reporting the use of CytoSorb therapy in patients with post-cpb SIRS. Due to a modulation of the cytokine response, CytoSorb may offer a potentially promising new treatment option for severe post-cpb SIRS that presents with hemodynamic instability and requires high doses of vasopressors. Systemic Inflammatory Response Syndrome in der Herzchirurgie: Neue Therapiemöglichkeiten durch den Einsatz eines Cytokin-Adsorbers während EKZ? Born F, Pichlmaier M, Peterß S, Khaladj N, Hagl C Kardiotechnik 2014;2:42-46 In this retrospective observational study in 40 patients undergoing a major cardio-surgical procedure with the use of Cardio-Pulmonary-Bypass (CPB) (n=20 with CPB, n=20 with CPB and an additional CytoSorb-adsorber in the circulation) the authors tested whether intraoperative treatment with CytoSorb has a positive effect on the development of post-operative SIRS. Results showed that CytoSorb contributes to a significant reduction in post-operative Literature List CytoSorb 12 Nov 18

13 SIRS in these patients and emphasizes the reliability and safety of CytoSorb in the setting of cardiac surgery Other indications Novel use of Cytosorb haemadsorption to provide biochemical control in liver impairment Dhokia VD, Madhavan D, Austin A, Morris CG Journal of Intensive Care Society 2018; epub In this case series the use of CytoSorb is described in the management of two patients with drug induced cholestasis and a third with alcoholic hepatitis and subsequent acute on chronic liver failure. CytoSorb was used in these patients to remove bilirubin and bile acids by supporting impaired excretory hepatic function. The first two patients were admitted to the intensive care unit specifically for a trial of CytoSorb therapy for alleviating their symptoms (including general malaise, anorexia and severe pruritus) and as a bridge to recovery of endogenous liver function. In all three cases, meaningful reductions in bilirubin (typically around 50% with 24 h CytoSorb therapy) and even more impressive reductions in bile acids were observed and, in conscious patients, were associated with animprovement in symptoms. The authors conclude that for patients with liver impairment where recovery might be expected or where transplantation is not clinically appropriate, and especially where an existing CRRT extracorporeal circuit is in use (? In AKI), clinicians may wish to consider CytoSorb as a convenient and effective means of reducing jaundice and clearing bile acids, although further studies are needed. The authors note that these cases suggest that CytoSorb should also be evaluated as an adjunct to support liver excretory functions in other arenas, such as acute liver failure or drug overdose Case reports Sepsis Successful use of combined blood purification techniques in splenectomised patient with septic shock in streptococcus pneumoniae infection - a case report. Sinkovic A, Kit B, Markota A. BMC Infect Dis 2018; 18(1): 433 Septic cardiomyopathy, caused by the cytokine storm, is a severe cardiac impairment in sepsis and is completely reversible if the patient survives. This is a case of a 52 yr old woman with a history of chemotherapy for lymphoma, splenectomy and autologous bone marrow transplantation, who suffered acute severe pneumococcal sepsis, septic shock and septic cardiomyopathy, resistant to pharmacological therapy including fluids and vasopressors. After 36 hrs of maximum standard therapies, it was decided to add extended hemodynamic monitoring, and continuous veno-venous hemofiltration plus Literature List CytoSorb 13 Nov 18

14 CytoSorb therapy because of the persistently resistant shock, to try to improve the hemodynamic situation and modulate the inflammatory response. After 24 hours of therapy the hemodynamic situation stabilized (including left ventricular systolic function), her IL-6 level dropped from 114 pg/ml to 14.2pg/ml and vasopressors could be ceased. This case shows that early removal of inflammatory cytokines enabled the reversal of circulatory failure and significant improvement of the septic cardiomyopathy resulting in improved hemodynamic status, lactacidosis and clinical outcome in this patient. Hemoadsorption in a Case of Severe Septic Shock and Necrotizing Fasciitis Caused by Nontraumatic Renal Rupture due to Pyelonephritis with Obstructive Uropathy Kousoulas L, Wittel U, Fichtner-Feigl S, Utzolino S. Case Rep Crit Care 2018: In this case a 25-year-old female presented with a four week history of acute worsening abdominal pain. She was found to have peritonitis, leukocytosis, severe lactic acidosis and pronounced anaemia, with imaging consistent with nontraumatic renal rupture with retroperitoneal abscess, perforation of the colon, and severe necrotizing fasciitis of the right lower limb. She underwent a right nephrectomy, a right hemicolectomy, surgical debridement of the retroperitoneum, and upper thigh amputation. Due to severe septic shock and rhabdomyolysis with acute renal failure combined treatment of hemoadsorption using Cytosorb (three cycles) and continuous venovenous hemodialysis (CVVHD) was started. Treatment was associated with rapid hemodynamic stabilization and decrease in IL-6 as well as myoglobin levels. Subsequently the patient recovered and was discharged home with no signs of infection and with normal renal function. The authors conclude that early treatment of the patient with Cytosorb led to the rapid hemodynamic and metabolic stabilization and preservation of the renal function, suggesting that hemoadsorption might be a rescue therapy in patients with severe septic shock and traumatic rhabdomyolysis. A case of viper snake bite presenting with gangrene and sepsis associated multi-organ failure, successfully treated with CytoSorb as an adjunct therapy a clinical experience Paul R, Jha BK, Shetty VK. J. Evid. Based Med. Healthc 2018; 5 (6): This is a case of a 32-year old male patient bitten by a viper who developed cellulitis, acute renal failure, and disseminated intravascular coagulation (DIC), septicemia and acute respiratory distress syndrome (ARDS). Because of necrotizing fasciitis and gangrene he had to have his lower limb amputated and was admitted to Intensive Care post op in septic shock (APACHE II 29 and SOFA 15). On the third post op day, in view of the multi-organ failure, he was Literature List CytoSorb 14 Nov 18

15 treated with Cytosorb, along with standard care as per the International Sepsis Guidelines. After two Cytosorb treatments each for 24-hours, renal, hemodynamic and respiratory parameters improved remarkably and returned to normal over 5 days. The authors state that Cytosorb along with standard care can be a safe and advantageous extracorporeal therapy option to treat snake bite patients with multi organ failure to help them recover. Use of CytoSorb in Traumatic Amputation of the Forearm and Severe Septic Shock Stelzer H, Grieb A, Mustafa K, Berger R. Case Reports in Critical Care 2017; Article ID This case study reports on a 49-year-old male patient admitted to hospital following traumatic amputation of his right forearm that was cut off at the elbow joint while working on a land fill site. After initial treatment for shock, he received immediate replantation and was transferred to the ICU. Due to the anticipated risk of a complex systemic infection, continuous renal replacement therapy in combination with CytoSorb was initiated. The patient received 6 CytoSorb treatments for 12 hrs each. During the course of the combined treatment, a rapid improvement in hemodynamics was noticed (noradrenaline dose could be halved during the first treatment), as well as a significant reduction in IL-6 (from >5000 to 43 pg/ml) and lactate levels (from 4 mmol/l to within the normal range). Despite recurring sepsis and the necessity for amputation, the patient clinically stabilized and underwent complete recovery 18 days after admission. Eearly treatment with a combination of CVVHDF and CytoSorb was accompanied by an attenuation of the systemic inflammatory reaction, which subsided without major or permanent organ damage, despite the impressive pathogen spectrum and the pronounced local damage. Use of Hemadsorption in a Case of Pediatric Toxic Shock Syndrome Berkes A, Szikszay E, Kappelmayer J, Kerenyi A, Szabo T, Ujhelyi L, Bari K, Balla G, Balla J Case Rep Crit Care 2017: This case report describes the successful treatment of toxic shock syndrome (a potentially fatal disease mediated by gram-positive bacterial toxins) in a 5 year old female pediatric Downs syndrome patient who presented with an inflamed area surrounding an insect bite, signs of systemic inflammation, and multiple organ failure. As attempts at resuscitation (including fluids, catecholamines and antibiotics), and immune modulatory therapies (including hydrocortisone, plasma exchange therapy and immunoglobulin therapy) were unsuccessful, renal replacement therapy supplemented with the CytoSorb adsorber was started which was associated with a rapid and significant stabilization in the hemodynamic situation, and a decrease in inflammatory mediators within hours after the initiation of therapy. The application of CytoSorb therapy was simple and safe. The use of CytoSorb proved potentially beneficial for removing bacterial toxins and inflammatory mediators and could Literature List CytoSorb 15 Nov 18

16 therefore play a role in the clinical management of toxic shock syndrome. Effect of extracorporeal cytokine removal on vascular barrier function in a septic shock patient David S, Thamm K, Schmidt BM, Falk CS, Kielstein JT J Intensive Care 2017;5:12 A 32-year-old female presented with septic shock and accompanying acute kidney injury to ICU. In spite of a broad anti-infective regimen, adequate fluid resuscitation, and high doses of inotropics and catecholamines, she remained in refractory hypotensive shock. The extraordinary severity of septic shock suggested an immense overwhelming host response assumingly accompanied by a notable cytokine storm. Thus, a CytoSorb adsorber was added to the dialysis circuit. To analyze the endothelial phenotype in vitro before and after extracorporeal cytokine removal, the authors tested the patient's serum on human umbilical vein endothelial cells (HUVECs) and the effect on the endothelial integrity was assessed. The authors found severe alterations in cell-cell contacts, the cytoskeletal architecture, and profound functional permeability changes (in other words clinical vascular leakage syndrome) when blood from the patient taken prior to the CytoSorb adsorber was added to the HUVECs. However, the endothelial barrier was protected from these profound adverse effects when blood serum was collected after the CytoSorb adsorber (cytokine removal) and added to the HUVECs. In conclusion the benefit of extracorporeal cytokine removal with CytoSorb in septic shock patients might-at least in part-be promoted via protection of vascular barrier function. Hemadsorption with Adult CytoSorb(R) in a Low Weight Pediatric Case Cirstoveanu CG, Barascu I, Mc Kenzie Stancu S Case Rep Crit Care 2017: This case study describes a nine-month old male infant admitted to the Neonatal Intensive Care Unit due to sepsis post cardiac surgery (Fallot tetralogy), and multi-system organ failure (MSOF), including liver and renal failure which was successfully treated by a combination of continuous hemodiafiltration (HDF) and hemoadsorption with CytoSorb. CytoSorb was added to the set up on day 9 due to increasing bilirubin levels. Over the 49 hour period of hemoadsorption plus CytoSorb, total bilirubin decreased from 54 to 14 mg/dl, the patient s general status improved considerably, accompanied by a rapid decrease in liver enzymes (aminotransferases). Hemodynamic status also improved and requirement for inotropes decreased rapidly during the two days of CytoSorb treatment. The patient was discharged home after 34 days of hospitalization, in good general health. This is the first published case of the successful use of CytoSorb treatment in such a young patient (9 months old, 9 kilos in weight). Literature List CytoSorb 16 Nov 18

17 Cytokine Adsorption in Septic Shock and Multiorgan Failure Following Major Obstetric Hemorrhage Withanage RK, Nilmini Wijesuriya N Journal of Case Reports 2017;7(1): In this case report a 38-year-old previously healthy patient developed septic shock with multi-organ failure following recurrent cardiac arrests due to massive obstetric hemorrhage. She had secondary hepatic impairment and acute kidney injury. Her medical care involved several surgical interventions and admission to intensive care. Continuous Renal Replacement Therapy was started on day 3 in ICU and CytoSorb was added to the hemofilter. Her liver enzymes (AST and ALT) and bilirubin started to decrease quite dramatically 12 hrs after the start of CytoSorb, her white blood cell count and CRP also decreased, and her vasopressor and inotropic support could also start to be tailored off. This case shows how a patient with major obstetric hemorrhage leading to recurrent cardiac arrests complicated by ischemic hepatocellular and kidney injury with secondary sepsis was managed successfully with the cytokine adsorber. Multiorgan-Failure-Following-Major-Obstetric-Hemorrhage-abstract.html Hybrid blood purification strategy in pediatric septic shock Bottari G, Taccone FS, Moscatelli A Crit Care 2016;20(1):366 In this letter to the editor, the case of a 12 year old girl with a history of acute lymphatic leukemia and recent chemotherapy admitted with fever and fatigue is described (cause of which later found to be klebsiella pneumonia from a central line infection). She was give fluid resuscitation, empiric antibiotics and admitted to ICU. Because of ongoing hypotension, epinephrine and norepinephrine were initiated, however she remained severely hypotensive. Continuous renal replacement therapy was started with a high cut off filter (Septex) along with a CytoSorb adsorber. After 48 hours a significant reduction in the vasopressors was observed, lactate decreased as did procalcitonin. The hybrid extracorporeal blood purification - EBP (combination of CytoSorb and Septex) was continued for 72 hours in total and the patient discharged after 10 days. No adverse events related to the procedure were observed. The authors state that the combination of hybrid EBP might have a synergistic effect in the setting of pediatric septic shock. Combination of ECMO and cytokine adsorption therapy for severe sepsis with cardiogenic shock and ARDS due to Panton-Valentine leukocidin-positive Staphylococcus aureus pneumonia and H1N1 Lees NJ, Rosenberg A, Hurtado-Doce AI, Jones J, Marczin N, Zeriouh M, Weymann A, Sabashnikov A, Simon AR, Popov AF J Artif Organs 2016;19(4): Literature List CytoSorb 17 Nov 18

18 Sepsis-induced cardiogenic shock in combination with severe acute respiratory failure represents a life-threatening combination that is often refractory to the conventional methods of treatment. Here the authors describe the case of a 33-year-old patient who developed acute cardiovascular collapse and ARDS secondary to superinfection of Panton-Valentine leukocidin-positive Staphylococcus aureus and H1N1 pneumonia who underwent successful combination therapy for severe sepsis-related cardiomyopathy and respiratory failure using extracorporeal membrane oxygenation and Cytosorb therapy. Use of the Cytosorb appeared to resut in rapid resolution of neutropenia, reversal of toxic shock and rapid weaning off of the high dose vasopressors. First case of toxic shock treated with haemoadsorption by CytoSorb in the Netherlands van der Linde GW, Grootendorst A Neth J Crit Care 2016;24(2):27-29 This case study reports on a 17-year-old male who reported a local rural hospital with complaints of pretibial pain in his right leg, after he accidentally cut his leg while in the fields a few days earlier. He was diagnosed with having a phlegmon with an abscess followed by surgical debridement with wound nettoyage with no clinical signs of subcutaneous emphysema or necrotising fasciitis. Postoperatively the patient s condition deteriorated and after admission to ICU he developed erythema, spreading from the right lower leg to the right upper leg, abdominal wall and the left leg, consistent with toxic shock syndrome and subsequent development of septic shock due to invasive S. aureus infection with respiratory failure, hemodynamic instability treated with vasopressors, hydrocortisone, antibiotic therapy. Due disease severity, CRRT was initiated with a CytoSorb adsorber with the only goal to remove cytokines (despite absence of acute kidney injury and no need for renal replacement therapy). Within six hours the erythema progression stopped and after 12 hours the need for vasopressors diminished. The erythema diminished after a few hours and had disappeared after 24 hours. After cessation of CytoSorb physicians concluded that the patient was no longer septic and diuretics were started because of fluid overload. Respiration improved, the ventilator support was weaned and the patient was extubated on day 5 after admission, within 72 hours of cessation of CRRT. In the authors opinion, the patient would have survived without CytoSorb, but they felt that his stay in the ICU might have been shortened by the CytoSorb adsorber Cytokine Reduction in the Setting of an ARDS-Associated Inflammatory Response with Multiple Organ Failure Traeger K, Schuetz C, Fischer G, Schroeder J, Skrabal C, Liebold A, Reinelt H Case Reports in Critical Care 2016;Vol 2016: Literature List CytoSorb 18 Nov 18

19 This case study reports on a 45-year-old male admitted with a small bowel obstruction due to torsion who was immediately scheduled for surgical intervention. At anesthetic induction, the patient aspirated and subsequently developed severe systemic inflammatory response syndrome with acute respiratory distress syndrome, and multiple organ failure requiring the use of ECMO, CRRT, antibiotics, and low dose steroids. Due to the rapid deterioration in his clinical status and a concurrent surge in inflammatory biomarkers, CytoSorb was added to the CRRT circuit. The combined treatment resulted in a rapid and significant reduction in the levels of circulating inflammatory mediators. This decrease was paralleled by marked clinical stabilization of the patient including a significant improvement in hemodynamic stability and a reduced need for norepinephrine and improved respiratory function, and indirect measures of capillary leak syndrome. The authors attribute the clinical improvement to the rapid control of the hyperinflammatory response and the reduction in the inflammatory mediators using a combination of CytoSorb and other therapies. CytoSorb treatment was safe and well tolerated, with no device-related adverse effects observed. CytoSorb, a novel therapeutic approach for patients with septic shock: a case report Hinz B, Jauch O, Noky T, Friesecke S, Abel P, Kaiser R Int J Artif Organs 2015;38(8):461-4 This case study reports on 72-year-old male patient with periodically recurring infectious episodes admitted with suspected urosepsis. Over the following hours his hemodynamic situation deteriorated markedly, with respiratorymetabolic acidosis, elevated inflammatory markers, severely disturbed coagulation, increased retention parameters, liver dysfunction, and confirmation of bacteria and leucocytes in his urine. After admission to the ICU in septic shock the patient received renal support with additional hemoadsorption using CytoSorb. Three CytoSorb sessions were run over the following days resulting in reductions in procalcitonin, C-reactive protein and bilirubin and a markedly reduced need for vasopressors and corresponding hemodynamic improvement (i.e., cardiac index, extravascular lung water). Due to a recurring inflammatory second hit episode, another CytoSorb session was run, resulting in the marked decrease in leukocytosis and liver (dys)function parameters. The rapid hemodynamic stabilization with reduction in vasopressor needs and reduction of the capillary leak as well as the quick reduction in infection markers were the main conclusions drawn from the use of CytoSorb in this patient. Additionally, treatment appeared to be safe and was well tolerated. Further studies are necessary to elucidate to what extent these favorable consequences are attributable to the adsorber itself. CytoSorb-friend or foe!! Pattnaik SK, Panda B. Indian J Crit Care Med 2015;19(5):296 Literature List CytoSorb 19 Nov 18

20 In this letter to the editor the authors refer to the case report by Basu et al. (PMID ), share their experiences with a similar patient treated with CytoSorb and discuss some of the intriguing points of their treatment. A 79- year-old male patient with severe septic shock (urosepsis) and multi-organ failure and an APACHE II score of 32, was started on CytoSorb therapy plus sustained low effusion dialysis along with standard surviving sepsis guidelines treatment. Within 3 days, hemodynamic parameters, ventilator requirements and urine output improved. APACHE II score improved after day 3 of therapy, and IL-6 levels reduced after the last session. Since the patient started to deteriorate clinically from day 5 day despite on-going supportive care, the authors bring up a possible immunosuppressive effect and express their concern as to whether CytoSorb therapy could be the cause of this. They note that randomized controlled trials are necessary to check the risk-benefit ratio of hemadsorption therapy in severely septic patients. Can cytokine adsorber treatment affect antibiotic concentrations? A case report Zoller M, Döbbeler G, Maier B, Vogeser M, Frey L, Zander J J Antimicrob Chemother 2015; 70(7): This case study reports on a patient with an excessive inflammatory response, septic shock and multi organ failure. Initial laparotomy revealed an ischemic bowel with peritonitis requiring immediate jejunum and colon segmental resection and ileotransverse colostomy. Intravenous antibiotic treatment was started with meropenem and linezolid. Due to the persistent excessive cytokine storm, four CytoSorb adsorbers were used over 96 hours. Therapy for septic shock included surgery, antibiotic treatment and CytoSorb which resulted in a substantial improvement in the patient s condition, including renal and liver function, and cardiorespiratory status. However, after 4 weeks and seven further repeat laparotomies, the patient died from multiple organ failure. The use of CytoSorb in this patient proved to be effective and safe. Of note, intra-patient variability of antibiotic levels was high with substantially lower peak levels for both antibiotics when CytoSorb was in use, pointing towards potential adsorption however, no negative impacts on the effectiveness of antibiotic therapy was detected. The authors suggest therapeutic drug monitoring wherever possible or, if not available, high loading doses or shorter intervals of administration be used to achieve adequate antibiotic levels with further studies needed. First successful combination of ECMO with cytokine removal therapy in cardiogenic septic shock: A case report Bruenger F, Kizner L, Weile J, Morshuis M, Gummert JF Int J Artif Organs 2015;38(2):113-6 Literature List CytoSorb 20 Nov 18